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Hattrick in deciphering of heart attack genes

Scientists of the University of Lübeck, Germany, together with other European and American colleagues, discovered six new genes responsible for the inheritance of heart attacks.

On February 8th, 2009, the online is-sue of the renowned scientific magazine Nature Genetics publishes three large-scale studies in parallel on these findings. The researchers of the European network Cardiogenics, coordinated by the University of Lübeck, are involved in each of the three publications.

The papers follow the success scientists had the year 2007 when they published the very first systematic genome-wide association study for the inheritance of myocardial infarction published in the respected New England Journal of Medicine (Samani et al. 2007). In this work as well as the current studies the complete human genome was scanned for hundreds of thousands genetic markers in thousands of patients. The scientists from Lübeck, Paris, and Boston tested for any single DNA marker, which stands for a tiny section of a chromosome, whether it was accumulated in heart attack patients.

The results add to a still growing list of genes which are responsible for heart attack. The researchers were supported by geneticists an clinicians from Kiel University. Together the two universities operate the biobank popgen. More than 5,000 coronary heart disease patients and healthy individuals from the north German federal state Schleswig-Holstein, who had previously donated blood at popgen, were incorporated into the new study.

New susceptibility locus for coronary artery disease on chromosome 3q22.3
The first of the three publications describes a study by Prof. Dr. Jeanette Erdmann and Prof. Dr. Heribert Schunkert with further colleagues, which was analysed by PD Dr. Inke R. König and Prof. Dr. Andreas Ziegler. In this study, one million genetic markers were evaluated in 1.200 patients with heart attacks (Erdmann et al. 2009). The subsequent replication studies in further 24,000 patients and healthy probands confirmed their initial suspicion: genes causing heart attacks are located on chro-mosomes 3 and 12. One of these genes, the so-called MRAS gene, is thought to play an important role in the biology of blood vessels. The second gene, HNF1A is in close relation to cholesterol metabolism. Both genes offer completely new attempts to understand the underlying pathogenetic mechanisms of heart attack. Ultimately, this knowledge will help to develop new therapies.
Genome wide haplotype association study identifies the SLC22A3-LPAL2 LPA genes cluster as a risk locus for coronary artery disease

The very innovative methodological approach of Dr. David Trégouët from Paris, first author of the second publication in Nature Genetics, looks at the effects of combinations of up to 10 genetic markers that are located in close proximity on the chromosomes (so-called haplotypes) on the risk of acquiring a heart attack (Trégouët et al. 2009). With this approach one can deduce an even higher density of genetic information than for single markers alone. With the increase in information density, the computer capacity necessary for data analysis also rises sharply. However, for the first time Dr. Trégouët employed the European EGEE Grid structure for such genetic analyses. The EGEE-Grid consists of 41,000 main processors (CPUs, central processing units) which provide storage of about five Petabyte (five million gigabyte) in total round-the-clock on hard disk every day. The net carries out 100,000 calculations simultaneously and is financed by the European Union. With this methodology the Cardiogenics consortium identified another region associated with heart attack risk, this time on chromosome 6. The LPA gene which is located in this region regulates the concentration of a certain lipoprotein, a particle which transports fatty acids, such as the lipoprotein (a), in the blood. This knowledge also can be possibly used in future for new therapeutical interventions.

Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants

The hattrick is completed by the work of the Myocardial Infarction Genetics Consor-tium, in which also the Cardiogenics scientists are involved (MIGen Consortium, 2009). With a similar methodical approach like in the first publication another three until now unknown genes associated with heart attack were identified on chromosomes 2, 6 and 21. To support this information and to gain statistical significance, 12,000 patients with heart attack were compared with 12,000 healthy persons. Furthermore this work shows that multiplying each others action the genetic markers in these disease-causing genes together more than double the risk for heart attacks. The higher the number of disease markers is that a patient carries; the higher is the risk to suffer from the disease. This knowledge will help to determine the illness risk in future for early prevention. The aim is therefore to reduce the risk for the arising of a heart attack.

About 750,000 people die of heart attack in Europe every year. The underlying illness of the coronary heart arteries and the heart attack are most frequent causes of death in most Western countries. Hereditary risk factors play a considerable role besides traditional risk factors like age, high blood pressure, fat metabolic disturbances, diabetes mellitus, smoking cigarette and overweight in the emergence of the disease.

The three above mentioned manuscripts add important pieces of the jigsaw to the picture of the inheritance of heart attack. Furthermore the work delivers insights into the emergence and mechanisms of the disease. Some of the findings are rather surprising, because these genes were, until now, not expected to be of any relevance for the development of heart attacks. In future, this knowledge will lead to an improved risk assessment for persons who have not yet fallen ill but who might carry the disease causing genes. Moreover, the findings offer new approaches for pharmacological prevention. From a European point of view it may be of interest that practically all myocardial infarction genes originate from the EU-project Cardiogenics, which is coordinated in Lübeck, Germany ( (1-4).

The new results allow a variety of scientific but also medical and clinical conclusions. Firstly, says Prof. Erdmann, the markers identified now offer new attempts to identify persons at risk of obtaining a heart disease. The aim is to concentrate preventative treatment on such people who have the highest risk for heart attacks. Secondly, PD Dr. König points out that this success would not have been possible without the development of novel statistical and information technological methods. Only through these approaches, we are able to find associations in this enormous bulk of data. Thirdly, we now see more clearly just how little we understand about the mechanisms leading to heart attacks, Prof. Schunkert comments on the work. Traditional risk factors, like high blood pressure, diabetes mellitus and increased cholesterol are important for the development of atherosclerosis but there still must be many undiscovered mechanisms that attribute to the disease. Hardly any of the heart attack genes identified thus far fits in the established clichés for the emer-gence of heart attack.

The question, why so many people in our population develop a heart attack, must be reevaluated considering these new findings. It is probable that completely new mechanisms will arise as the emergence of heart disease begins with variants in these newly discovered heart attack genes. However, new mechanisms also mean new approaches in prophylaxis and treatment of heart attacks. It is up to scientists around the world now to elucidate the mechanisms by which these genes cause heart attacks and to explore this knowledge for better prevention and treatment.

1) Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, Dixon RJ, Meitinger T, Braund P, Wichmann HE, Barrett JH, König IR, Stevens SE, Szymczak S, Tregouet DA, Iles MM, Pahlke F, Pollard H, Lieb W, Cambien F, Fischer M, Ouwehand W, Blankenberg S, Balmforth AJ, Baessler A, Ball SG, Strom TM, Braenne I, Gieger C, Deloukas P, Tobin MD, Ziegler A, Thompson JR, Schunkert H; WTCCC and the Cardiogenics Consortium. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007 Aug 2;357(5):443-53.
2) Erdmann J, Großhennig A, Braund PS, König IR, Hengstenberg C, Hall AS, Linsel-Nitschke P, Kathiresan S, Wright B, Trégouët DA, Cambien F, Bruse P, Aherrahrou Z, Wagner AK, Stark K, Schwartz SM, Salomaa V, Elosua R, Melander O, Voight BF, O'Donnell CJ, Peltonen L, Siscovick DS, Altshuler D, Merlini PA, Peyvandi F, Bernardinelli L, Ardissino D, Schillert A, Blankenberg S, Zeller T, Wild P, Schwarz DF, Tiret L, Perret C, Schreiber S, El Mokhtari NE, Schä-fer A, März W, Renner W, Bugert P, Klüter H, Schrezenmeir J, Rubin D, Ball SG, Balmforth AJ, Wichmann HE, Meitinger T, Fischer M, Meisinger C, Baumert J, Peters A, Ouwehand WH, Italian Atherosclerosis, Thrombosis, and Vascular Biology Working Group, Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium, Cardiogenics Consortium, Deloukas P, Thompson JR, Ziegler A, Samani NJ & Schunkert H. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nature Genetics (in press).
3) Trégouët DA, König IR, Erdmann J, Munteanu A, Braund PS, Hall AS, Großhennig A, Linsel-Nitschke P, Perret C, DeSuremain M, Meitinger T, Wright BJ, Preuss M, Balmforth AJ, Ball SG, Meisinger C, Germain C, Evans A, Arveiler D, Luc G, Ruidavets JB, Morrison C, van der Harst P, Schreiber S, Neureuther K, Schäfer A, Bugert P, El Mokhtari NE, Schrezenmeir J, Stark K, Rubin D, Wichmann HE, Hengstenberg C, Ouwehand WH, Wellcome Trust Case Control Consortium, Cardiogenics Consortium, Ziegler A, Tiret L, Thompson JR, Cambien F, Schunkert H & Samani NJ. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nature Genetics (in press).

4) MIGen Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nature Genetics (in press).


Prof. Dr. rer. nat. Jeanette Erdmann
(head, Laboratory for Molecular Genetics at the MK II)
Universität zu Lübeck
Medizinische Klinik II
Ratzeburger Allee 160
23538 Lübeck
phone: +49 (0)451 500 4857, +49 (0)174 4744602
PD Dr. rer. biol. hum. Inke R. König
(vice-director of the Institut für Medizinische Biometrie und Statistik)
Universität zu Lübeck
Institut für Medizinische Biometrie und Statistik
Ratzeburger Allee 160
23538 Lübeck
phone: +49 (0)451 500 6869
Prof. Dr. med. Heribert Schunkert
(director of the MK II)
Universität zu Lübeck
Medizinische Klinik II
Ratzeburger Allee 160
23538 Lübeck
phone: +49 (0)451 500 2501

Rüdiger Labahn | idw
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